Controlling Epileptic Activity by Modulating Putrescine Metabolism

Glial mechanisms regulate neuronal excitability through multiple mechanisms, including the control of extracellular inhibitory signaling. One such mechanism is the Glu/GABA exchange process, in which glutamate uptake is coupled to GABA release, with GABA being synthesized from the polyamine putrescine, placing putrescine at a central position in metabolic pathways that may influence epileptiform activity. Here, we examined how pharmacological manipulation of key enzymes of putrescine metabolism affects seizure-like activity in the low-[Mg²⁺] in vitro model of frontotemporal epilepsy, complemented by in vivo recordings in the non-convulsive absence epilepsy model Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats. Increasing putrescine availability by inhibiting spermidine synthase with trans-4-methylcyclohexylamine significantly reduced both the duration and appearance of seizure-like events. Strikingly, simultaneous inhibition of monoamine oxidase B (MAO-B) and diamine oxidase (DAO) with deprenyl and aminoguanidine almost completely abolished seizure-like events in vitro and markedly suppressed spike-wave discharges in WAG/Rij rats. This effect was largely reversed by blockade of GAT-2/3 transporters with SNAP-5114, suggesting the presence and significant anti-epileptic potential of a MAO-B- and DAO-independent putrescine-GABA synthesis pathway. Together, these findings indicate that the anticonvulsant effects of putrescine metabolism arise from the coordinated engagement of multiple parallel pathways rather than from a single dominant enzymatic route. Putrescine thus appears to function as a metabolic hub whose increased availability can be channeled into several anticonvulsant processes, suggesting that therapeutic strategies enhancing putrescine-dependent inhibitory pathways at the network level may offer promising avenues for the modulation of epileptiform activity.